Abstract
Treatment of cancer cells with anticancer drugs often fails to achieve complete remission. Yet, such drug treatments may induce alteration in the tumor's gene expression patterns, including those of Cancer/Testis Antigens (CTA). The degradation products of such antigens can be presented as HLA peptides on the surface of the tumor cells and be developed into anticancer immunotherapeutics. For example, the DNA methyl transferase inhibitor, 5-aza-2'-deoxycytidine (Decitabine) has limited antitumor efficacy, yet it induces the expression of many genes, including CTAs that are normally silenced in the healthy adult tissues. In this study, the presentation of many new HLA peptides derived from CTAs and induced by Decitabine was demonstrated in three human Glioblastoma cell lines. Such presentation of CTA-derived HLA peptides can be exploited for development of new treatment modalities, combining drug treatment with anti-CTA targeted immunotherapy. The Decitabine-induced HLA peptidomes include many CTAs that are not normally detected in healthy tissues or in cancer cells, unless treated with the drug. In addition, the study included large-scale analyses of the simultaneous effects of Decitabine on the transcriptomes, proteomes and HLA peptidomes of the human Glioblastoma cells. It demonstrates the poor correlations between these three levels of gene expression, both in their total levels and in their response to the drug. The proteomics and HLA peptidomics data are available via ProteomeXchange with identifier PXD003790 and the transcriptomics data are available via GEO with identifier GSE80137.
Highlights
Grade IV astrocytoma, called glioblastoma multiforme (GBM)1, is the most common and aggressive primary brain
Most of the Cancer/Testis Antigens (CTA) promoters are methylated in the healthy adult tissues, such regulation is often lost in the tumor cells
Number of upregulated CTAs proteome analyses identified about 7500 proteins and the HLA class I peptidome analyses resulted in above 25,000 identified HLA peptides (Table I)
Summary
Grade IV astrocytoma, called glioblastoma multiforme (GBM), is the most common and aggressive primary brain. Most of the CTA promoters are methylated in the healthy adult tissues, such regulation is often lost in the tumor cells These epigenetic abnormalities, prevalent in cancer cells, induce differential expression of oncogenes and CTAs as side effects of the loss of cellular control [27,28,29,30]. This research aimed to promote the development of a reliable method for selection of potential candidates for cancer immunotherapy, especially CTAs induced by drugs, such as Decitabine It followed the effect of the drug on the transcriptomes, proteomes, and the HLA peptidomes of cultured human GBM cells, resulting in the discovery of large sets of druginduced CTAs. The obtained data are potentially useful for advancing the development of new approaches for immunotherapy, based on the induction by drugs of tumor antigens that are not normally expressed by the cancer cells and can be used for combined drug and immunotherapy cancer treatment
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